Cell: Dr. Yang Daping et al. found that pain has an unexpected direct protective effect

Pain has long been considered one of the most reliable tools in evolution to detect the presence of injury and signal that something is wrong
.
It's like a wake-up call that tells us to stop and pay attention to our bodies
.

But what if pain isn't just a wake-up call? What if pain itself is a form of protection?

October 14, 2022, Isaac M.
of Harvard Medical School.
Chiu and Yang Daping published a research paper
in Cell titled: Nociceptor neurons direct goblet cells via a CGRP-RAMP1 axis to drive mucus production and gut barrier protection.

This study shows that the pain-receptor nerves in the gut are normally able to regulate the presence of protective mucus and stimulate goblet cells in the intestine to secrete more mucus in an inflammatory state, thereby directly protecting the
intestines.
The study details the steps of this complex signaling cascade, showing that the pain-receptor nerve can directly crosstalk with the intestinal goblet cells
.

Isaac Chiu, corresponding author of the paper and associate professor of immunobiology at Harvard Medical School, said the study demonstrates that pain may protect us in a more direct way, not just by detecting potential harm and sending signals to the brain
.
This study reveals how pain-regulating nerves
in the gut communicate with intestinal epithelial cells.
This means that the nervous system plays a key role
in intestinal barrier maintenance and inflammation protection mechanisms, in addition to giving us unpleasant sensations.

Yang Daping (left), Isaac Chiu (right)

Yang Daping spent two years of postdoctoral training in Qian Youcun's laboratory at the Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, during which he published an immunity paper and found that the disordered lung microecology promotes a new mechanism
of pulmonary fibrosis pathology by regulating the expression of IL-17B.
In 2020, Yang Daping joined Isaac Chiu's lab and began research
on the gut-brain axis that mediates pain and inflammation.

Direct conversation

Our intestines and respiratory tract are lined with goblet cells, named for their goblet appearance, that secrete protective gelatinous mucus that protects the surface of organs from damage
.
This latest study shows that protective mucus is released when the goblet cells of the intestine interact directly with the pain-receptor nerves in the gut
.

The team observed that mice lacking pain-sensing nerves produced less protective mucus and their gut microbial composition changed, i.
e.
, the balance between beneficial and harmful microbes was disrupted
.
To understand how this protective crosstalk occurs, the research team analyzed the behavior
of goblet cells in the presence of pain-receptor nerves and the absence of pain-receptor nerves.

The team found that the surface of goblet cells contains a receptor called RAMP1, which ensures that the cells respond to adjacent pain-sensitive nerves that are activated
by dietary and microbial signals, as well as mechanical stress, chemical stimulation or drastic temperature changes.

Experiments further showed that when the pain-receptor nerve is stimulated, the RAMP1 receptor binds to the neuropeptide CGRP, which is secreted
by nearby pain-receptor nerves.
They found that these RAMP1 receptors are also present in the goblet cells of humans and mice, thus making them responsive
to pain signals.

Experiments further showed that the presence of certain gut microbes activated the release of CGRP to maintain intestinal homeostasis
.

Isaac Chiu says the findings tell us that pain-receptor nerves in the gut are triggered not only by acute inflammation, but also by normal conditions
.
As long as there are gut microbes around it, it seems to stimulate these pain-sensing nerves, causing goblet cells to secrete mucus
.
This feedback loop ensures that microbes send signals to nerves, which regulate mucus secretion and mucus that maintains gut microbial health
.

The study also showed that in addition to the presence of microbes, dietary factors also play a role
in activating pain-receptor nerves.
When the researchers gave mice capsaicin, their pain-sensing nerves were rapidly activated and prompted goblet cells to secrete large amounts of mucus
.

In contrast, mice were more susceptible to colitis
, either lacking the pain-receptive nerve or missing CGRP's RAMP1 receptor in goblet cells.
This also explains why people with dysbiosis are more likely to develop colitis
.
When the researchers injected the pain signal CGRP with mice lacking pain-receptor nerves, mucus secretion increased rapidly, and the treatment protected the mice from colitis
even in the absence of pain-receptor nerves.
This finding suggests that CGRP is a key stimulatory factor
leading to a signaling cascade of protective mucus secretion.

Dr.
Yang Daping, the first author of the paper, said that pain is a common symptom of chronic inflammation of the intestines, such as colitis, and this study shows that this pain also plays a direct protective role
.

Pain relief treatments may have drawbacks

One of the main symptoms of people with intestinal inflammation is pain, so painkillers are often used to block pain and thus reduce the feeling of
pain.
However, the study showed that when colitis occurred, mice lacking pain-sensing nerves suffered more severe injuries
.
This suggests that this pain signal may act as a nerve reflex for direct protection
.
This pain-relieving treatment can have some harmful consequences
.
So, how can pain be relieved without causing other harm? This is a direction
worth studying.

In addition, goblet cells play other roles in the gut, producing antimicrobial substances that protect the gut from pathogens
.
This also raises some new questions: Can the pain-receptor nerve regulate these anti-pathogen functions of goblet cells?

Finally, Dr.
Yang said that the team will also explore whether disruption of the CGRP signaling pathway plays a role
in patients with a genetic predisposition to inflammatory bowel disease.

Links to papers:

https://doi.
org/10.
1016/j.
cell.
2022.
09.
024